There have been numerous previous attempts to explore the effects of immunopotentiation in general on the growth of tumor cells in humans. Observations were made as early as the 1890s that in some instances, although a rather small percentage, administration of immunopotentiating agents to patients resulted in remission of their tumors (Coley, W. B., Am J Med Sci (1893) 105:487; Trans Am Surg Assoc (1894) 12:183; Proc R Soc Med (Surg Sect) (1909) 3:1; for reviews, see Oettgen, H. F., et al., in "Important Advances in Oncology," DeVita B. T., Jr., et al., eds., J. B. Lippincott Company, Philadelphia, Pa. (1987) pp. 105-132; Hersh, E. M., in "Immunity to Cancer," Reif, A. E., et al., eds., Academic Press, Orlando, Fla. (1985) pp. 443-452.
In addition, it has been observed that inflammation of cancer cells, but not of normal cells in a subject by administration of bacterial cells or their constituents can result in tumor regression. This has been assumed due to the differing nature of the components released from cancer cells during inflammation as compared to normal cells (Yamamoto, N., et al., Cancer Res (1987) 47:2008-2013; Yamamoto, N., et al., Cancer Res (1988) 48:6044-6049). In addition, a number of immunopotentiators have been considered as potential therapeutic agents for not only infectious diseases, but also in the treatment of neoplasms (Ruszala-Mallon, V., et al., Int J Immuno Pharmac (1988) 10:497-510).
Despite this modest early success at the turn of the century, the use of immunopotentiators for treatment of tumors has not been actively pursued in view of the putatively more effective methods of radiotherapy, chemotherapy, and surgery. Nevertheless, some attention has been paid sporadically to this approach, and the results of studies heretofore have been inconclusive as to describing ways to predict success or failure using such treatments and therefore to devise protocols which will assure success. Local treatment of noninvasive bladder cancer with the putative immunostimulator BCG has, however, been reported (Cockett, A. T., et al., Proc Clin Biol Res (1989) 303:455). There is also recent evidence that the concomitant administration of 5-fluorouracil and levamisole (an immunopotentiator) may be effective in the treatment of Duke's C colon cancer (Moertel, C. G., et al., New Engl J Med (1990) 322:399-401). Although levamisole is known to have immunopotentiating properties, it is not clear whether the effectiveness of this combination is due to immunopotentiation or to some other form of synergy (ibid).
One of the nonspecific immunopotentiators which has been used recently is a preparation from the bacterium Serratia marcescens which contains small ribosome particles and membrane vesicles in a suspending buffer. This preparation is in clinical trials and utilizes the trademark "ImuVert," is described in PCT/US87/01397, and is marketed by Cell Technologies of Boulder, Colo. Although this preparation was used in a number of studies in support of the invention described and claimed herein, it is merely representative of a large class of immunopotentiators which are effective with respect to macrophages.
It is also known that tumor cell preparations may contain effector cells derived from the immune system. Generally, these may be classified as lymphocytes and macrophages. The presence of macrophage effector cells at the site of the tumor is essential for the success of the method of the invention as will be described further below.
It has now been found that immunopotentiators which are directed to macrophage populations are effective in causing tumor necrosis if the tumor is of a type that can be successfully treated using chemotherapy or other treatment methods which result in tumor cell destruction and provided that the tumor has actually been treated with chemotherapy or said alternative protocols prior to the administration of the immunopotentiator.